Type 17 immunity: novel insights into intestinal homeostasis and autoimmune pathogenesis driven by gut-primed T cells

Abstract

The IL-23 signaling pathway in both innate and adaptive immune cells is vital for orchestrating type 17 immunity, which is marked by the secretion of signature cytokines such as IL-17, IL-22, and GM-CSF. These proinflammatory mediators play indispensable roles in maintaining intestinal immune equilibrium and mucosal host defense; however, their involvement has also been implicated in the pathogenesis of chronic inflammatory disorders, such as inflammatory bowel diseases and autoimmunity. However, the implications of type 17 immunity across diverse inflammation models are complex. This review provides a comprehensive overview of the multifaceted roles of these cytokines in maintaining gut homeostasis and in perturbing gut barrier integrity, leading to acute and chronic inflammation in various models of gut infection and colitis. Additionally, this review focuses on type 17 immunity interconnecting multiple organs in autoimmune conditions, with a particular emphasis on the pathogenesis of autoimmune arthritis and neuroinflammation driven by T cells primed within the gut microenvironment.

Keywords: Gut-brain axis; Gut-joint axis; IL-23; Inflammatory bowel diseases (IBD); Th17; cDCIL-23.

Fig. 1

Three-step developmental model of IL-23-producing cDCs. The activation of Notch2 signaling serves as the initial trigger for the differentiation process of EpCAM⁺ DCIR⁺ cDCs. This is followed by the induction of CIA-DC signature genes, such as LyzM, in cDCs through lymphotoxins from ILC3s and their recruitment into tertiary lymphoid organs. Ultimately, the terminal differentiation of these cells necessitates the involvement of retinoic acid signaling, which is pivotal for endowing them with robust ability to produce IL-23

Fig. 2

Similar gene expression profiles between Il23a-Venus⁺ EpCAM⁺ DCIR2⁺ CD103^- CD11b^- cDCs (cDC_IL-23) and LyzM^hi CIA-DCs. A Reanalysis of the scRNA-seq atlas of SILP cDCs (E-MTAB-9522) [10]. Marker gene expression associated with CIA-DC and Il23a-Venus⁺ cDCs was projected via UMAP analysis of SILP cDCs. B The gene set score of the Il23a-Venus⁺ cDC signature was calculated via the scanpy.tl.score_genes function and projected via UMAP analysis [190]. The top 100 upregulated genes sorted by adjusted p value in bulk RNA-seq data of Il23a-Venus⁺ cDCs compared with CD103⁺ CD11b⁺ cDCs were used as the signature genes of Il23a-Venus⁺ cDCs (DRA016070) [8]

Fig. 3

Spatiotemporal regulation of the IL-23‒IL-22 axis during C. rodentium infection. A During the early phases of C. rodentium infection, the IL-23‒IL-22 axis in tertiary lymphoid organs, such as ILFs and CPs, is critical. Specifically, IL-23-producing EpCAM⁺ DCIR2⁺ CD103^- CD11b^- cDCs (cDC_IL-23) activated by TLR signaling via pathogen-associated molecular patterns play a pivotal role in stimulating IL-22 expression by ILC3s. B During its later phase, in addition to the interaction between cDC_IL-23 and ILC3s in tertiary lymphoid organs, the engagement of macrophages and IECs in the activation of Th17 and/or ILC3s within the lamina propria emerges as an additional significant aspect in combating C. rodentium infection. Notably, CX3CR1⁺ macrophages and IECs facilitate IL-22 expression by Th17 cells through the presentation of antigens, costimulatory molecules, and cytokines such as IL-1β, thereby fostering sustained activation of gut epithelial cells and eventual elimination of C. rodentium infection

Fig. 4

The opposing roles of Th17-producing cytokines in IBD pathogenesis. Th17-producing cytokines, including IL-22, IL-17, and GM-CSF, influence diverse biological processes and can act both protectively and pathogenically in inflammatory bowel disease (IBD). The effects of these cytokines can be categorized into direct effects on IECs and indirect effects via myeloid subsets. In the context of their direct effects on IECs, these cytokines regulate the gut microbiota through the production of antimicrobial peptides and increase the fucosylation of membrane proteins on IECs. These cytokines also promote gut stem cell turnover, inhibit apoptosis induced by injury, and strengthen tight junctions between IECs, thereby maintaining gut integrity. Collectively, these effects play a protective role in IBD. In the indirect effect mediated through myeloid cell subsets, IL-22 and IL-17 enhance chemokine production by IECs, which in turn recruit neutrophils and monocytes. GM-CSF is involved in neutrophil activation, monocyte maturation, and eosinophil differentiation. The recruited and activated myeloid cells contribute to bacterial killing through phagocytosis. However, these cells can also mediate inflammation via cytokine production (i.e., IL-23 and IL-1β) and tissue destruction, thereby exacerbating the pathology of IBD

Fig. 5

Spatiotemporal regulation of IL-23 expression in mononuclear phagocytes during acute and chronic gut inflammation. A In acute inflammation during infection, IL-23 expression is limited to cDC_IL-23, which is located within GALTs, such as ILFs and CPs. Although macrophages in the lamina propria may also become activated during infection, their production of IL-23 is typically inhibited by IL-10 and Lag3 from Tregs, as well as potentially other environmental factors. Consequently, after elimination of mucosal pathogens, the immune response mediated by type 17 immune cells swiftly returns to baseline levels. B In IBD, genetic and environmental factors alter the functionality of macrophages in the lamina propria, either directly or through pathways involving IL-10 and Lag3 from Tregs. These alterations lead to excessive activation of macrophages, which become hypersensitive to CD40 and TLR stimulation from activated T cells and the gut microbiota, respectively. As a result, these macrophages produce large amounts of IL-23. Elevated IL-23 then promotes the differentiation of pathogenic Th17 cells, which drive intestinal inflammation and compromise the barrier function of IECs. IL-23 also impairs the suppressive functions of Tregs, reducing their ability to regulate macrophage activity. This cascade creates a positive feedback loop between T cells and macrophages through the CD40‒IL-23 axis. Continuous stimulation from the gut microbiota, due to impaired barrier function, further augments chronic inflammation driven by type 17 immune responses